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Special Issue "Frontiers in Nucleic Acid Chemistry"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Molecular Diversity".

Deadline for manuscript submissions: closed (15 July 2015)

Special Issue Editor

Guest Editor
Prof. Dr. Ramon Eritja

Institute for Advanced Chemistry of Catalonia, IQAC-CSIC, CIBER-BBN, Jordi Girona 18-26, 08034 Barcelona, Spain
Website | E-Mail
Interests: nucleic acid chemistry; DNA and RNA analogs: synthesis applications, molecular tools; RNA interference; DNA nanotechnology; G-quadruplex; Triplex, artificial DNA

Special Issue Information

Dear Colleagues,

Nucleic acids are the key molecules for transmitting genetic inheritance. The identification of DNA as the basis of genetic material and the elucidation of its structure stimulated the development of protocols for synthesizing defined oligonucleotides. Today, synthetic oligonucleotides that contain genetically encoded information have become emerging drugs and essential tools for biological, biomedical, and nanotechnology research. Novel oligonucleotide derivatives with tailored properties have been developed. Most of these new properties were obtained by modifying the structure or by introducing selected molecules, thus resulting in oligonucleotide conjugates or chimeras. In addition, artificial or modified nucleic acids, with novel hybridization properties, have been developed. The study of the properties of such nucleic acids brings together many different branches of science, such as molecular biology, chemistry, biochemistry, pharmaceuticals, medicine, materials science, and synthetic biology.

This Special Issue of Molecules will concentrate on the latest developments in nucleic acids chemistry. For this Special Issue, we encourage authors to submit research papers and comprehensive reviews describing nucleic acid derivatives with novel or improved structural and/or biomedical properties.

Prof. Dr. Ramon Eritja
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.


Keywords

  • modified oligonucleotides
  • artificial nucleic acids
  • xeno nucleic acids
  • synthetic genes
  • oligonucleotide conjugates
  • G-quadruplex
  • i-motif
  • triplex
  • Antisense
  • siRNA
  • RNA interference
  • DNA nanobiotechnology
  • nanomaterials
  • aptamers
  • fluorescent nucleic acids
  • locked nucleic acids
  • unlocked nucleic acids
  • DNA repair
  • Base-modified DNA
  • DNA polymerase
  • Circular nucleic acids
  • NMR of nucleic acids
  • Biophysical studies

Related Special Issue

Published Papers (17 papers)

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Research

Jump to: Review

Open AccessArticle Binding of Harmine Derivatives to DNA: A Spectroscopic Investigation
Molecules 2017, 22(11), 1831; doi:10.3390/molecules22111831
Received: 28 September 2017 / Revised: 20 October 2017 / Accepted: 24 October 2017 / Published: 27 October 2017
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Abstract
Harmine belongs to a group of β-carboline alkaloids endowed with antitumor properties. Harmine and its derivatives are thought to bind to DNA and interfere with topoisomerase activities. We investigated the base-dependent binding of harmine, and three of its synthetic anticancer-active derivatives to the
[...] Read more.
Harmine belongs to a group of β-carboline alkaloids endowed with antitumor properties. Harmine and its derivatives are thought to bind to DNA and interfere with topoisomerase activities. We investigated the base-dependent binding of harmine, and three of its synthetic anticancer-active derivatives to the genomic DNA from calf thymus and two synthetic 20-mer double helices, the poly(dG-dC)·poly(dG-dC) and the poly(dA-dT)·poly(dA-dT), by means of UV-Vis and circular dichroism (CD) spectroscopies. The data show that the DNA binding and stabilising properties of the investigated derivatives are base pair-dependent. These results could be used as a guide to design and develop further bioactive analogues. Full article
(This article belongs to the collection New Frontiers in Nucleic Acid Chemistry)
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Open AccessArticle The Molecular Effect of Diagnostic Absorbed Doses from 131I on Papillary Thyroid Cancer Cells In Vitro
Molecules 2017, 22(6), 993; doi:10.3390/molecules22060993
Received: 14 April 2017 / Revised: 12 June 2017 / Accepted: 13 June 2017 / Published: 15 June 2017
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Abstract
Diagnostic whole-body scan is a standard procedure in patients with thyroid cancer prior to the application of a therapeutic dose of 131I. Unfortunately, administration of the radioisotope in a diagnostic dose may decrease further radioiodine uptake—the phenomenon called “thyroid stunning”. We estimated
[...] Read more.
Diagnostic whole-body scan is a standard procedure in patients with thyroid cancer prior to the application of a therapeutic dose of 131I. Unfortunately, administration of the radioisotope in a diagnostic dose may decrease further radioiodine uptake—the phenomenon called “thyroid stunning”. We estimated radiation absorbed dose-dependent changes in genetic material, in particular in the sodium iodide symporter (NIS) gene promoter, and the NIS protein level in a K1 cell line derived from the metastasis of a human papillary thyroid carcinoma exposed to 131I in culture. The different activities applied were calculated to result in absorbed doses of 5, 10 and 20 Gy. Radioiodine did not affect the expression of the NIS gene at the mRNA level, however, we observed significant changes in the NIS protein level in K1 cells. The decrease of the NIS protein level observed in the cells subjected to the lowest absorbed dose was paralleled by a significant increase in 8-oxo-dG concentrations (p < 0.01) and followed by late activation of the DNA repair pathways. Our findings suggest that the impact of 131I radiation on thyroid cells, in the range compared to doses absorbed during diagnostic procedures, is not linear and depends on various factors including the cellular components of thyroid pathology. Full article
(This article belongs to the collection New Frontiers in Nucleic Acid Chemistry)
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Open AccessArticle Synthesis and Biological Evaluation of Triazolyl 13α-Estrone–Nucleoside Bioconjugates
Molecules 2016, 21(9), 1212; doi:10.3390/molecules21091212
Received: 28 July 2016 / Revised: 2 September 2016 / Accepted: 6 September 2016 / Published: 10 September 2016
Cited by 2 | PDF Full-text (2934 KB) | HTML Full-text | XML Full-text
Abstract
2′-Deoxynucleoside conjugates of 13α-estrone were synthesized by applying the copper-catalyzed alkyne–azide click reaction (CuAAC). For the introduction of the azido group the 5′-position of the nucleosides and a propargyl ether functional group on the 3-hydroxy group of 13α-estrone were chosen. The best yields
[...] Read more.
2′-Deoxynucleoside conjugates of 13α-estrone were synthesized by applying the copper-catalyzed alkyne–azide click reaction (CuAAC). For the introduction of the azido group the 5′-position of the nucleosides and a propargyl ether functional group on the 3-hydroxy group of 13α-estrone were chosen. The best yields were realized in our hands when the 3′-hydroxy groups of the nucleosides were protected by acetyl groups and the 5′-hydroxy groups were modified by the tosyl–azide exchange method. The commonly used conditions for click reaction between the protected-5′-azidonucleosides and the steroid alkyne was slightly modified by using 1.5 equivalent of Cu(I) catalyst. All the prepared conjugates were evaluated in vitro by means of MTT assays for antiproliferative activity against a panel of human adherent cell lines (HeLa, MCF-7 and A2780) and the potential inhibitory activity of the new conjugates on human 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1) was investigated via in vitro radiosubstrate incubation. Some protected conjugates displayed moderate antiproliferative properties against a panel of human adherent cancer cell lines (the protected cytidine conjugate proved to be the most potent with IC50 value of 9 μM). The thymidine conjugate displayed considerable 17β-HSD1 inhibitory activity (IC50 = 19 μM). Full article
(This article belongs to the collection New Frontiers in Nucleic Acid Chemistry)
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Open AccessArticle DNA Three Way Junction Core Decorated with Amino Acids-Like Residues-Synthesis and Characterization
Molecules 2016, 21(9), 1082; doi:10.3390/molecules21091082
Received: 5 July 2016 / Revised: 8 August 2016 / Accepted: 10 August 2016 / Published: 23 August 2016
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Abstract
Construction and physico-chemical behavior of DNA three way junction (3WJ) functionalized by protein-like residues (imidazole, alcohol and carboxylic acid) at unpaired positions at the core is described. One 5′-C(S)-propargyl-thymidine nucleotide was specifically incorporated on each strand to react through a post
[...] Read more.
Construction and physico-chemical behavior of DNA three way junction (3WJ) functionalized by protein-like residues (imidazole, alcohol and carboxylic acid) at unpaired positions at the core is described. One 5′-C(S)-propargyl-thymidine nucleotide was specifically incorporated on each strand to react through a post synthetic CuACC reaction with either protected imidazolyl-, hydroxyl- or carboxyl-azide. Structural impacts of 5′-C(S)-functionalization were investigated to evaluate how 3WJ flexibility/stability is affected. Full article
(This article belongs to the collection New Frontiers in Nucleic Acid Chemistry)
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Open AccessArticle Chemical Incorporation of Chain-Terminating Nucleoside Analogs as 3′-Blocking DNA Damage and Their Removal by Human ERCC1-XPF Endonuclease
Molecules 2016, 21(6), 766; doi:10.3390/molecules21060766
Received: 13 May 2016 / Accepted: 3 June 2016 / Published: 11 June 2016
Cited by 1 | PDF Full-text (2286 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Nucleoside/nucleotide analogs that lack the 3′-hydroxy group are widely utilized for HIV therapy. These chain-terminating nucleoside analogs (CTNAs) block DNA synthesis after their incorporation into growing DNA, leading to the antiviral effects. However, they are also considered to be DNA damaging agents, and
[...] Read more.
Nucleoside/nucleotide analogs that lack the 3′-hydroxy group are widely utilized for HIV therapy. These chain-terminating nucleoside analogs (CTNAs) block DNA synthesis after their incorporation into growing DNA, leading to the antiviral effects. However, they are also considered to be DNA damaging agents, and tyrosyl-DNA phosphodiesterase 1, a DNA repair enzyme, is reportedly able to remove such CTNA-modifications of DNA. Here, we have synthesized phosphoramidite building blocks of representative CTNAs, such as acyclovir, abacavir, carbovir, and lamivudine, and oligonucleotides with the 3′-CTNAs were successfully synthesized on solid supports. Using the chemically synthesized oligonucleotides, we investigated the excision of the 3′-CTNAs in DNA by the human excision repair cross complementing protein 1-xeroderma pigmentosum group F (ERCC1-XPF) endonuclease, which is one of the main components of the nucleotide excision repair pathway. A biochemical analysis demonstrated that the ERCC1-XPF endonuclease cleaved 2–7 nt upstream from the 3′-blocking CTNAs, and that DNA synthesis by the Klenow fragment was resumed after the removal of the CTNAs, suggesting that ERCC1-XPF participates in the repair of the CTNA-induced DNA damage. Full article
(This article belongs to the collection New Frontiers in Nucleic Acid Chemistry)
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Open AccessArticle DNA Scaffolded Silver Clusters: A Critical Study
Molecules 2016, 21(2), 216; doi:10.3390/molecules21020216
Received: 28 December 2015 / Revised: 1 February 2016 / Accepted: 2 February 2016 / Published: 17 February 2016
Cited by 2 | PDF Full-text (4301 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Fluorescent silver nanoclusters (Ag-NCs) are in prominence as novel sensing materials due to their biocompatibility, photostability, and molecule-like optical properties. The present work is carried out on an array (17 sequences) of 16 bases long cytosine rich, single stranded DNA templates 5′-C3
[...] Read more.
Fluorescent silver nanoclusters (Ag-NCs) are in prominence as novel sensing materials due to their biocompatibility, photostability, and molecule-like optical properties. The present work is carried out on an array (17 sequences) of 16 bases long cytosine rich, single stranded DNA templates 5′-C3XiC3XiiC3XiiiC3Xiv-3′ where i, ii, iii, iv correspond to T/G/C deoxynucleobases (with default base A). Among all the oligonucleotides, a sequence C3AC3AC3TC3G (3T4G) has been identified, which grows three different near-infrared-emitting NC species with absorption/emission maxima at ~620/700 (species I), 730/800 (species II), and 830 (Species III) nm, respectively. The nature of the spectral profiles, along with relevant parameters namely absorption maximum (\(\lambda_{abs}^{max}\)), emission maximum (\(\lambda_{em}^{max}\)), anisotropy (r), lifetime (\(\tau\)), circular dichroism spectral data are used to understand the microenvironments of the fluorescent NC species I, II, and III. DNA:Ag stiochiometric, pH and solvent dependent studies proved that i-motif scaffolds with different folding topologies are associated with the growth of these three species and a certain concentration of silver and H+ favor the growth of species III. Size exclusion chromatographic measurements provided similar indications that a folded, more compact, classic i-motif template is associated with the formation of the longer NIR (~830 nm) absorbing species. This study provides a more definitive approach to design and obtain a targeted DNA templated Ag-NC with required emission properties for biophysical and cellular applications. Full article
(This article belongs to the Special Issue Frontiers in Nucleic Acid Chemistry)
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Open AccessArticle A 7-Deazaadenosylaziridine Cofactor for Sequence-Specific Labeling of DNA by the DNA Cytosine-C5 Methyltransferase M.HhaI
Molecules 2015, 20(11), 20805-20822; doi:10.3390/molecules201119723
Received: 6 August 2015 / Revised: 3 November 2015 / Accepted: 10 November 2015 / Published: 23 November 2015
Cited by 4 | PDF Full-text (3630 KB) | HTML Full-text | XML Full-text
Abstract
DNA methyltransferases (MTases) catalyze the transfer of the activated methyl group of the cofactor S-adenosyl-l-methionine (AdoMet or SAM) to the exocyclic amino groups of adenine or cytosine or the C5 ring atom of cytosine within specific DNA sequences. The DNA adenine-N6 MTase
[...] Read more.
DNA methyltransferases (MTases) catalyze the transfer of the activated methyl group of the cofactor S-adenosyl-l-methionine (AdoMet or SAM) to the exocyclic amino groups of adenine or cytosine or the C5 ring atom of cytosine within specific DNA sequences. The DNA adenine-N6 MTase from Thermus aquaticus (M.TaqI) is also capable of coupling synthetic N-adenosylaziridine cofactor analogues to its target adenine within the double-stranded 5′-TCGA-3′ sequence. This M.TaqI-mediated coupling reaction was exploited to sequence-specifically deliver fluorophores and biotin to DNA using N-adenosylaziridine derivatives carrying reporter groups at the 8-position of the adenine ring. However, these 8-modified aziridine cofactors were poor substrates for the DNA cytosine-C5 MTase from Haemophilus haemolyticus (M.HhaI). Based on the crystal structure of M.HhaI in complex with a duplex oligodeoxynucleotide and the cofactor product, we synthesized a stable 7-deazaadenosylaziridine derivative with a biotin group attached to the 7-position via a flexible linker. This 7-modified aziridine cofactor can be efficiently used by M.HhaI for the direct, quantitative and sequence-specific delivery of biotin to the second cytosine within 5′-GCGC-3′ sequences in short duplex oligodeoxynucleotides and plasmid DNA. In addition, we demonstrate that biotinylation by M.HhaI depends on the methylation status of the target cytosine and, thus, could provide a method for cytosine-C5 DNA methylation detection in mammalian DNA. Full article
(This article belongs to the Special Issue Frontiers in Nucleic Acid Chemistry)
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Open AccessArticle Synthesis, Hydrolysis, and Protonation-Promoted Intramolecular Reductive Breakdown of Potential NRTIs: Stavudine α-P-Borano-γ-P-N-l-tryptophanyltriphosphates
Molecules 2015, 20(10), 18808-18826; doi:10.3390/molecules201018808
Received: 16 August 2015 / Revised: 15 September 2015 / Accepted: 21 September 2015 / Published: 16 October 2015
Cited by 2 | PDF Full-text (968 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Phosphorus-modified prodrugs of dideoxynucleoside triphosphates (ddNTPs) have shown promise as pronucleotide strategies for improving antiviral activity compared to their parent dideoxynucleosides. Borane modified NTPs offer a promising choice as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). However, the availability of α-P-borano-γ-P-substituted
[...] Read more.
Phosphorus-modified prodrugs of dideoxynucleoside triphosphates (ddNTPs) have shown promise as pronucleotide strategies for improving antiviral activity compared to their parent dideoxynucleosides. Borane modified NTPs offer a promising choice as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). However, the availability of α-P-borano-γ-P-substituted NTP analogs remains limited due to challenges with synthesis and purification. Here, we report the chemical synthesis and stability of a new potential class of NRTI prodrugs: stavudine (d4T) 5′-α-P-borano-γ-P-N-L-tryptophanyltriphosphates. One-pot synthesis of these compounds was achieved via a modified cyclic trimetaphosphate approach. Pure Rp and Sp diastereomers were obtained after HPLC separation. Based on LC-MS analysis, we report degradation pathways, half-lives (5–36 days) and mechanisms arising from structural differences to generate the corresponding borano tri- and di-phosphates, and H-phosphonate, via several parallel routes in buffer at physiologically relevant pH and temperature. Here, the major hydrolysis products, d4T α-P-boranotriphosphate Rp and Sp isomers, were isolated by HPLC and identified with spectral data. We first propose that one of the major degradation products, d4T H-phosphonate, was generated from the d4T pronucleotides via a protonation-promoted intramolecular reduction followed by a second step nucleophilic attack. This report could provide valuable information for pronucleotide-based drug design in terms of selective release of target nucleotides. Full article
(This article belongs to the Special Issue Frontiers in Nucleic Acid Chemistry)
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Open AccessArticle Comparative Incorporation of PNA into DNA Nanostructures
Molecules 2015, 20(9), 17645-17658; doi:10.3390/molecules200917645
Received: 6 August 2015 / Revised: 13 September 2015 / Accepted: 21 September 2015 / Published: 23 September 2015
Cited by 1 | PDF Full-text (2450 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
DNA has shown great promise as a building material for self-assembling nanoscale structures. To further develop the potential of this technology, more methods are needed for functionalizing DNA-based nanostructures to increase their chemical diversity. Peptide nucleic acid (PNA) holds great promise for realizing
[...] Read more.
DNA has shown great promise as a building material for self-assembling nanoscale structures. To further develop the potential of this technology, more methods are needed for functionalizing DNA-based nanostructures to increase their chemical diversity. Peptide nucleic acid (PNA) holds great promise for realizing this goal, as it conveniently allows for inclusion of both amino acids and peptides in nucleic acid-based structures. In this work, we explored incorporation of a positively charged PNA within DNA nanostructures. We investigated the efficiency of annealing a lysine-containing PNA probe with complementary, single-stranded DNA sequences within nanostructures, as well as the efficiency of duplex invasion and its dependence on salt concentration. Our results show that PNA allows for toehold-free strand displacement and that incorporation yield depends critically on binding site geometry. These results provide guidance for the design of PNA binding sites on nucleic acid nanostructures with an eye towards optimizing fabrication yield. Full article
(This article belongs to the Special Issue Frontiers in Nucleic Acid Chemistry)
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Open AccessArticle Synthesis and Evaluation of a Rationally Designed Click-Based Library for G-Quadruplex Selective DNA Photocleavage
Molecules 2015, 20(9), 16446-16465; doi:10.3390/molecules200916446
Received: 24 July 2015 / Revised: 22 August 2015 / Accepted: 31 August 2015 / Published: 10 September 2015
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Abstract
DNA containing repeating G-rich sequences can adopt higher-order structures known as G-quadruplexes (G4). These structures are believed to form within telomeres and the promoter regions of some genes, particularly in a number of proto-oncogenes, where they may play a role in regulating transcription.
[...] Read more.
DNA containing repeating G-rich sequences can adopt higher-order structures known as G-quadruplexes (G4). These structures are believed to form within telomeres and the promoter regions of some genes, particularly in a number of proto-oncogenes, where they may play a role in regulating transcription. Alternatively, G4 DNA may act as a barrier to replication. To investigate these potential biological roles, probes that combine highly selective G4 DNA targeting with photocleavage activity can allow temporal detection of G4 DNA, providing opportunities to obtain novel insights about the biological roles of G4 DNA. We have designed, synthesized, and screened a small library of potential selective G-quadruplex DNA photocleavage agents incorporating the G-quadruplex targeting moiety of 360A with known photocleavage groups linked via “click” chemistry. Full article
(This article belongs to the Special Issue Frontiers in Nucleic Acid Chemistry)
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Open AccessArticle Mixed-Sequence Recognition of Double-Stranded DNA Using Enzymatically Stable Phosphorothioate Invader Probes
Molecules 2015, 20(8), 13780-13793; doi:10.3390/molecules200813780
Received: 1 July 2015 / Revised: 23 July 2015 / Accepted: 24 July 2015 / Published: 29 July 2015
Cited by 3 | PDF Full-text (2359 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Development of probes that allow for sequence-unrestricted recognition of double-stranded DNA (dsDNA) continues to attract much attention due to the prospect for molecular tools that enable detection, regulation, and manipulation of genes. We have recently introduced so-called Invader probes as alternatives to more
[...] Read more.
Development of probes that allow for sequence-unrestricted recognition of double-stranded DNA (dsDNA) continues to attract much attention due to the prospect for molecular tools that enable detection, regulation, and manipulation of genes. We have recently introduced so-called Invader probes as alternatives to more established approaches such as triplex-forming oligonucleotides, peptide nucleic acids and polyamides. These short DNA duplexes are activated for dsDNA recognition by installment of +1 interstrand zippers of intercalator-functionalized nucleotides such as 2′-N-(pyren-1-yl)methyl-2′-N-methyl-2′-aminouridine and 2′-O-(pyren-1-yl)methyluridine, which results in violation of the nearest neighbor exclusion principle and duplex destabilization. The individual probes strands have high affinity toward complementary DNA strands, which generates the driving force for recognition of mixed-sequence dsDNA regions. In the present article, we characterize Invader probes that are based on phosphorothioate backbones (PS-DNA Invaders). The change from the regular phosphodiester backbone furnishes Invader probes that are much more stable to nucleolytic degradation, while displaying acceptable dsDNA-recognition efficiency. PS-DNA Invader probes therefore present themselves as interesting probes for dsDNA-targeting applications in cellular environments and living organisms. Full article
(This article belongs to the Special Issue Frontiers in Nucleic Acid Chemistry)
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Open AccessCommunication Synthesis and Enzymatic Incorporation of Modified Deoxyuridine Triphosphates
Molecules 2015, 20(8), 13591-13602; doi:10.3390/molecules200813591
Received: 2 June 2015 / Revised: 16 July 2015 / Accepted: 20 July 2015 / Published: 24 July 2015
Cited by 5 | PDF Full-text (1128 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
To expand the chemical functionality of DNAzymes and aptamers, several new modified deoxyuridine triphosphates have been synthesized. An important precursor that enables this aim is 5-aminomethyl dUTP, whereby the pendent amine serves as a handle for further synthetic functionalization. Five functional groups were
[...] Read more.
To expand the chemical functionality of DNAzymes and aptamers, several new modified deoxyuridine triphosphates have been synthesized. An important precursor that enables this aim is 5-aminomethyl dUTP, whereby the pendent amine serves as a handle for further synthetic functionalization. Five functional groups were conjugated to 5-aminomethyl dUTP. Incorporation assays were performed on several templates that demand 2–5 sequential incorporation events using several commercially available DNA polymerases. It was found that Vent (exo-) DNA polymerase efficiently incorporates all five modified dUTPs. In addition, all nucleoside triphosphates were capable of supporting a double-stranded exponential PCR amplification. Modified PCR amplicons were PCR amplified into unmodified DNA and sequenced to verify that genetic information was conserved through incorporation, amplification, and reamplification. Overall these modified dUTPs represent new candidate substrates for use in selections using modified nucleotide libraries. Full article
(This article belongs to the Special Issue Frontiers in Nucleic Acid Chemistry)
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Open AccessArticle The Influence of the Terminal Phosphorothioate Diester Bond on the DNA Oxidation Process. An Experimental and Theoretical Approach
Molecules 2015, 20(7), 12400-12411; doi:10.3390/molecules200712400
Received: 6 March 2015 / Revised: 12 June 2015 / Accepted: 24 June 2015 / Published: 8 July 2015
Cited by 1 | PDF Full-text (1546 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In this study, the influence of the terminal phosphorothioate (PT) internucleotide bond in ds-DNA on the oxidation process was taken into consideration. The interaction of UV with the targeted oligonucleotide leads to an electron ejection and radical cation “hole” migration through the
[...] Read more.
In this study, the influence of the terminal phosphorothioate (PT) internucleotide bond in ds-DNA on the oxidation process was taken into consideration. The interaction of UV with the targeted oligonucleotide leads to an electron ejection and radical cation “hole” migration through the ds-DNA until it is trapped irreversibly in a suitable place. Phosphorothiate internucleotide bonds were detected in the bacterial genome; however, their role is still unclear. In this study a PAGE analysis of irradiated ds-DNA showed that the degradation rea ction was slowed down by the presence PT next to the anthraquinone moiety. Further, theoretical study shows that [RP] AQ-PS-dG can adopt a slightly lower ionisation potential energy and triplet excited state with a subsequent slightly higher adiabatic electron affinity value in comparison with [SP] AQ-PS-dG and AQ-PO-dG. Moreover, the energy gap between HOMO and LUMO, indicated the radical stabilisation properties of [RP] AQ-PS-dG, which can hinder the charge transfer through ds-DNA. Full article
(This article belongs to the Special Issue Frontiers in Nucleic Acid Chemistry)
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Open AccessArticle Modulation of the RNA Interference Activity Using Central Mismatched siRNAs and Acyclic Threoninol Nucleic Acids (aTNA) Units
Molecules 2015, 20(5), 7602-7619; doi:10.3390/molecules20057602
Received: 13 January 2015 / Revised: 21 April 2015 / Accepted: 22 April 2015 / Published: 24 April 2015
Cited by 5 | PDF Full-text (1604 KB) | HTML Full-text | XML Full-text
Abstract
The understanding of the mechanisms behind nucleotide recognition by Argonaute 2, core protein of the RNA-induced silencing complex, is a key aspect in the optimization of small interfering RNAs (siRNAs) activity. To date, great efforts have been focused on the modification of certain
[...] Read more.
The understanding of the mechanisms behind nucleotide recognition by Argonaute 2, core protein of the RNA-induced silencing complex, is a key aspect in the optimization of small interfering RNAs (siRNAs) activity. To date, great efforts have been focused on the modification of certain regions of siRNA, such as the 3'/5'-termini and the seed region. Only a few reports have described the roles of central positions flanking the cleavage site during the silence process. In this study, we investigate the potential correlations between the thermodynamic and silencing properties of siRNA molecules carrying, at internal positions, an acyclic L-threoninol nucleic acid (aTNA) modification. Depending on position, the silencing is weakened or impaired. Furthermore, we evaluate the contribution of mismatches facing either a natural nucleotide or an aTNA modification to the siRNA potency. The position 11 of the antisense strand is more permissive to mismatches and aTNA modification, in respect to the position 10. Additionally, comparing the ON-/OFF-target silencing of central mismatched siRNAs with 5'-terminal modified siRNA, we concluded: (i) central perturbation of duplex pairing features weights more on potency rather than silencing asymmetry; (ii) complete bias for the ON-target silencing can be achieved with single L-threoninol modification near the 5'-end of the sense strand. Full article
(This article belongs to the Special Issue Frontiers in Nucleic Acid Chemistry)
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Review

Jump to: Research

Open AccessReview Evolution of Complex Target SELEX to Identify Aptamers against Mammalian Cell-Surface Antigens
Molecules 2017, 22(2), 215; doi:10.3390/molecules22020215
Received: 20 December 2016 / Accepted: 24 January 2017 / Published: 30 January 2017
Cited by 8 | PDF Full-text (2434 KB) | HTML Full-text | XML Full-text
Abstract
The demand has increased for sophisticated molecular tools with improved detection limits. Such molecules should be simple in structure, yet stable enough for clinical applications. Nucleic acid aptamers (NAAs) represent a class of molecules able to meet this demand. In particular, aptamers, a
[...] Read more.
The demand has increased for sophisticated molecular tools with improved detection limits. Such molecules should be simple in structure, yet stable enough for clinical applications. Nucleic acid aptamers (NAAs) represent a class of molecules able to meet this demand. In particular, aptamers, a class of small nucleic acid ligands that are composed of single-stranded modified/unmodified RNA/DNA molecules, can be evolved from a complex library using Systematic Evolution of Ligands by EXponential enrichment (SELEX) against almost any molecule. Since its introduction in 1990, in stages, SELEX technology has itself undergone several modifications, improving selection and broadening the repertoire of targets. This review summarizes these milestones that have pushed the field forward, allowing researchers to generate aptamers that can potentially be applied as therapeutic and diagnostic agents. Full article
(This article belongs to the collection New Frontiers in Nucleic Acid Chemistry)
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Open AccessReview Therapeutic Oligonucleotides Targeting Liver Disease: TTR Amyloidosis
Molecules 2015, 20(10), 17944-17975; doi:10.3390/molecules201017944
Received: 13 July 2015 / Revised: 23 September 2015 / Accepted: 23 September 2015 / Published: 30 September 2015
Cited by 8 | PDF Full-text (2548 KB) | HTML Full-text | XML Full-text
Abstract
The liver has become an increasingly interesting target for oligonucleotide therapy. Mutations of the gene encoding transthyretin (TTR), expressed in vast amounts by the liver, result in a complex degenerative disease, termed familial amyloid polyneuropathy (FAP). Misfolded variants of TTR are linked to
[...] Read more.
The liver has become an increasingly interesting target for oligonucleotide therapy. Mutations of the gene encoding transthyretin (TTR), expressed in vast amounts by the liver, result in a complex degenerative disease, termed familial amyloid polyneuropathy (FAP). Misfolded variants of TTR are linked to the establishment of extracellular protein deposition in various tissues, including the heart and the peripheral nervous system. Recent progress in the chemistry and formulation of antisense (ASO) and small interfering RNA (siRNA) designed for a knockdown of TTR mRNA in the liver has allowed to address the issue of gene-specific molecular therapy in a clinical setting of FAP. The two therapeutic oligonucleotides bind to RNA in a sequence specific manner but exploit different mechanisms. Here we describe major developments that have led to the advent of therapeutic oligonucleotides for treatment of TTR-related disease. Full article
(This article belongs to the Special Issue Frontiers in Nucleic Acid Chemistry)
Open AccessReview G-Quadruplex Forming Oligonucleotides as Anti-HIV Agents
Molecules 2015, 20(9), 17511-17532; doi:10.3390/molecules200917511
Received: 31 July 2015 / Revised: 10 September 2015 / Accepted: 16 September 2015 / Published: 22 September 2015
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Abstract
Though a variety of different non-canonical nucleic acids conformations have been recognized, G-quadruplex structures are probably the structural motifs most commonly found within known oligonucleotide-based aptamers. This could be ascribed to several factors, as their large conformational diversity, marked responsiveness of their folding/unfolding
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Though a variety of different non-canonical nucleic acids conformations have been recognized, G-quadruplex structures are probably the structural motifs most commonly found within known oligonucleotide-based aptamers. This could be ascribed to several factors, as their large conformational diversity, marked responsiveness of their folding/unfolding processes to external stimuli, high structural compactness and chemo-enzymatic and thermodynamic stability. A number of G-quadruplex-forming oligonucleotides having relevant in vitro anti-HIV activity have been discovered in the last two decades through either SELEX or rational design approaches. Improved aptamers have been obtained by chemical modifications of natural oligonucleotides, as terminal conjugations with large hydrophobic groups, replacement of phosphodiester linkages with phosphorothioate bonds or other surrogates, insertion of base-modified monomers, etc. In turn, detailed structural studies have elucidated the peculiar architectures adopted by many G-quadruplex-based aptamers and provided insight into their mechanism of action. An overview of the state-of-the-art knowledge of the relevance of putative G-quadruplex forming sequences within the viral genome and of the most studied G-quadruplex-forming aptamers, selectively targeting HIV proteins, is here presented. Full article
(This article belongs to the Special Issue Frontiers in Nucleic Acid Chemistry)
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